Naturally occurring opiates such as morphine and codeine possess an N-methyl group. Varying this substituent produces profound pharmacological effects and there are a number of clinically relevant, semi-synthetic opiates in which the N-methyl group has been replaced by other alkyl moieties. Substituents such as allyl, cyclopropylmethyl and cyclobutylmethyl typically endow antagonist properties, though agonist activity is restored with longer alkyl groups such as phenethyl. For example, Nalorphine (1) (FIG. 1), which has an N-allyl group, has mixed agonist and antagonist activity, while N-phenethylnormorphine (2) acts as an μ agonist with 10 fold greater potency than morphine itself.[1] The combination of an N-allyl or N-cyclopropylmethyl group and some additional C-ring modifications (6-keto and 14-hydroxy functionality) affords the potent antagonists, Naloxone (3) and Naltrexone (4), respectively. N-demethylation of natural opiates is therefore a key chemical transformation in the synthesis of semi-synthetic opiates.
N-Demethylation of natural opiates has been achieved in many ways including the use of reagents such as cyanogen bromide (von Braun reaction),[2] chloroformates[3] and diethyl azodicarboxylate,[4] as well as procedures utilising photochemistry,[5] electrochemistry[6] and microorganisms.[7] It has also been shown that the FeSO4.7H2O-mediated non-classical Polonovski reaction is also effective in the N-demethylation of several opiate alkaloids.[8] These and other methods for the N-demethylation of alkaloids have been the subject of a recent review.[9]
The FeSO4.7H2O reaction is described, for instance, in WO 02/16367. In that process, the tertiary N-methylamine of the N-methylated opiate is converted to the N-methyl, N-oxide by reaction with a suitable oxidising agent. The N-methyl, N-oxide is then converted to the secondary amine (ie the methyl group is removed) by reaction with a reducing agent such as FeSO4.7H2O.
The N-demethylation step is typically problematic; requiring the use of toxic and expensive reagents and proceeds in low chemical yield.
Recently, a one-pot synthetic method for the N-demethylation of morphine and tropane alkaloids has been disclosed by Hudlicky's group in Carroll et al, Adv. Synth. Catal. 2008, 350, 2984-2992[10] and WO 2009/003272[11]. The method discloses the use of Pd(0), Pd(II) or Cu(II) complexes, with or without an oxidant, in various solvents in order to N-demethylate hydrocodone, codeine and tropine or to N-demethylate and N-acylate in one step. Remarkably, the technique does not rely on the preparation of the N-methyl, N-oxide. In fact, the authors of Carrol et al note that the Cu(II) catalysed procedure does not N-demethylate hydrocodone N-oxide. They state at pp 2985-2986:                Unlike the conditions reported by Scammells, which require the initial formation and isolation of the corresponding N-oxide prior to subsequent demethylation, the present process constitutes a one-pot procedure. In fact, we found that prior formation of the corresponding hydrocodone N-oxide and subsequent treatment with Cu(OAc)2 and (NH4)2S2O8 resulted in no demethylation, suggesting that the Cu catalysed process follows a different mechanism.        
In a later article (Chaudhary et al, Collect. Czech. Chem. Commun. 2009, 74 (7-8), 1179-1193),[12] Hudlicky and co-workers also commented on the limited scope of the abovementioned[10,11] methodology. They state:                “ . . . we had observed that palladium-catalyzed demethylations seemed to be limited to hydrocodone and a few tropane-type alkaloids”.        
There is a need for reagents and procedures to effect the N-demethylation of opiate alkaloids cleanly and in good yield.